The present invention concerns a new multi-step process for preparing 1,2-diamino compounds from 1,2-epoxides, in particular 1,2-diamino compounds useful as inhibitors of viral or bacterial neuraminidases, a new step of that multi-step process for preparing 2-aminoalcohols from 1,2-epoxides, a new step for the transformation of a 2-aminoalcohol into a 1,2-diamino compound as well as specific intermediates useful in that multi-step process.
PCT Patent Publication No. 96/26933 describes a large class of compounds useful as inhibitors of viral or bacterial neuraminidases and their preparation. These compounds comprise a six membered partially unsaturated carbocyclic or heterocyclic ring system, which can be substituted by several different substituents.
PCT Patent Publication No. 98/07685 discloses various methods for preparing compounds of the above class which are cyclohexene carboxylate derivatives. A particularly interesting compound is (3R,4R,5S)-5-amino-4-acetylamino-3-(1-ethyl-propoxy)-cyclohex-1-ene-carboxylic acid ethyl ester (C. U. Kim et al., J. Am.Chem. Soc., 1997, 119, 681-690). A method of preparation of that 1,2-diamino compound in 10 steps starting from shikimic acid, or in 12 steps starting from quinic acid, is described by J. C. Rohloff et al., J. Org. Chem.,1998, 63, 4545-4550. The 10 step method involves a final 4-step reaction sequence from the 1,2-epoxide (1S,5R,6R)-5-(1-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester via three potentially highly toxic and explosive azide intermediates. Dedicated know-how and expensive equipment are required to perform such a process. In a technical process it is preferable to avoid use of azide reagents and azide intermediates.
The problem to be solved by the present invention therefore was to find an azide-free process for preparing 1,2-diamino compounds from 1,2-epoxides.
That problem has been solved by the invention as described below and as defined in the appended claims.
The invention provides a process for preparing 1,2-diamino compounds of formula
and pharmaceutically acceptable addition salts thereof wherein,
R1, R1xe2x80x2, R2 and R2xe2x80x2, independently of each other, are H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, heterocyclyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, aryl, aryl-lower alkyl, aryl-lower alkenyl, or aryl-lower alkynyl, or
R1 and R2, R1 and R2xe2x80x2, R1xe2x80x2 and R2 or R1xe2x80x2 and R2xe2x80x2 taken together with the two carbon atoms to which they are bound, are a carbocyclic or heterocyclic ring system, or
R1 and R1xe2x80x2 or R2 and R2xe2x80x2 taken together with the carbon atom to which they are bound, are a carbocyclic or heterocyclic ring system,
with the proviso that at least one of R1, R1xe2x80x2, R2 and R2xe2x80x2 is not H, and
R3 and R4, independently from each other, are H or a substituent of an amino group, with the proviso that not both R3 and R4, are H,
which process is characterized in that it comprises the steps of
a) reacting a 1,2-epoxide of formula
xe2x80x83wherein R1, R1xe2x80x2, R2 and R2xe2x80x2 are as above with an amine of formula R5NHR6 wherein R5 and R6, independently of each other, are H, or a substituent of an amino group, with the proviso that not both R5 and R6 are H to form a 2-aminoalcohol of formula 
xe2x80x83wherein R1, R1xe2x80x2, R2 , R2xe2x80x2, R5 and R6 are as above
b) converting the 2-aminoalcohol of formula (III) into a 2-aminoalcohol of formula 
xe2x80x83wherein R1, R1xe2x80x2, R2 and R2xe2x80x2 are as above,
c) transforming the 2-aminoalcohol of formula (IV) into a 1,2-diamino compound of formula 
xe2x80x83wherein R1, R1xe2x80x2, R2, R2xe2x80x2, R5 and R6 are as above
d) acylating the free amino group in position 1 of the 1,2-diamino compound of formula (V) to form an acylated 1,2-diamino compound of formula 
xe2x80x83wherein R1, R1xe2x80x2, R2R2xe2x80x2, R3, R4, R5 and R6 are as above and finally
e) deprotecting the amino group in position 2 of formula (VI) to form the 1,2-diamino compound of formula (I).
If desired, the resulting 1,2-diamino compound of formula (I) can be further transformed into a pharmaceutically acceptable addition salt.
The term xe2x80x9calkylxe2x80x9d means a straight chain or branched saturated alkyl group with 1-20, preferably 1-12, C-atoms, which can carry one or more substituents.
The term xe2x80x9calkenylxe2x80x9d means a straight chain or branched alkenyl group with 2-20, preferably 2-12, C-atoms, which can carry one or more substituents.
The term xe2x80x9calkynylxe2x80x9d means a straight chain or branched alkynyl group with 2-20, preferably 2-12, C-atoms, which can carry one or more substituents.
The term xe2x80x9ccycloalkylxe2x80x9d signifies a saturated, cyclic hydrocarbon group with 3-12, preferably 5-7, C-atoms, which can carry one or more substituents.
The term xe2x80x9carylxe2x80x9d denotes a mono-nuclear or di-nuclear aromatic group which can carry one or more substituents, such as, for example, phenyl, substituted phenyl, naphthyl, or substituted naphthyl.
The term xe2x80x9cheterocyclylxe2x80x9d means a saturated or unsaturated monocyclic or bicyclic group with 1 or 2 nitrogen, sulfur and/or oxygen atoms such as, for example pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, isobenzofuranyl, furanyl, tetrahydrofuranyl, thiofuranyl, dihydrothiofuranyl, benzo[b]dihydrofuranyl, tetrahydrothiofuranyl, thioxanyl, dioxanyl, dithianyl, chromanyl, isochromanyl, dithiolanyl, pyridyl, pyperidyl, imidazolidinyl, pyrrolidinyl, quinolyl or isoquinolyl, which can carry one or more substituents.
The term xe2x80x9ccarbocyclic ring systemxe2x80x9d means a cyclic alkyl group with 3-12, preferably 5-7, C-atoms, which can include one or two carbon-carbon double bonds, and which can carry one or more substituents, such as for example cyclopentene, substituted cyclopentene, cyclohexene, substituted cyclohexene, cycloheptene, or substituted cycloheptene.
The term xe2x80x9cheterocyclic ring systemxe2x80x9d means a monocyclic or bicyclic group with 1 or 2 nitrogen, sulfur and/or oxygen atoms, which can include one or two double bonds and carry one or more substituents, as exemplified above under the term xe2x80x9cheterocyclylxe2x80x9d, for example tetrahydropyran, dihydropyran, substituted dihydropyran, tetrahydrofuran, isobenzotetrahydrofuran, thioxan, 1,4-dioxane, dithian, dithiolan, piperidine, or piperazine.
Suitable substituents on the above groups are those which are inert in the reactions involved.
Examples of suitable substituents on such alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, heterocyclyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, aryl, or aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, are lower alkyl, lower alkoxy, lower alkyl carboxylate, carboxylic acid, carboxamide, N-(mono/di-lower alkyl)-carboxamide.
Examples of suitable substituents on such a carbocyclic or heterocyclic ring system are alkyl of 1 to 12 C-atoms, alkenyl of 2 to 12 C-atoms, alkynyl of 2 to 12 C-atoms, alkoxy of 1 to 12 C-atoms, alkyl of 1 to 12 C-atoms-carboxylate, carboxylic acid, carboxamide, N-(mono/di-alkyl of 1 to 12 C-atoms)-carboxamide. Preferred substituents are lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, carboxylic acid, lower alkyl carboxylate, carboxamide, N-(mono/di-lower alkyl)-carboxamide.
The term xe2x80x9clowerxe2x80x9d here denotes a group with 1-6, preferably 1-4, C-atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl and its isomers and hexyl and its isomers. Examples of lower alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, iso-butoxy, sec.-butoxy, tert.-butoxy and 1-ethyl-propoxy. Examples of lower alkyl carboxylates are methyl carboxylate, ethyl carboxylate, propyl carboxylate, isopropyl carboxylate and butyl carboxylate. Examples of lower alkanoyl groups are acetyl, propionyl and butyryl.
In accordance with the present invention, the term xe2x80x9csubstituent of an amino groupxe2x80x9d refers to any substituents conventionally used to hinder the reactivity of an amino group, as described in Green, T., xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Chapter 7, John Wiley and Sons, Inc., 1991, 315-385, herein incorporated by reference. Such preferred substituents are acyl, alkyl, alkenyl, alkynyl, aryl-lower alkyl, silyl methyl wherein silyl is trisubstituted with lower alkyl, lower alkenyl, lower alkynyl and/or aryl. Advantageously the reactivity of the amino group can also be hindered by protonation e.g. with Lewis acids, including H+.
The term xe2x80x9cacylxe2x80x9d means alkanoyl, preferably lower alkanoyl, alkoxy-carbonyl, preferably lower alkoxy-carbonyl, aryloxy-carbonyl or aroyl such as benzoyl.
In a preferred embodiment the invention comprises a process for preparing 4,5-diamino-shikimic acid derivatives of formula 
and pharmaceutically acceptable addition salts thereof wherein
R11 is an optionally substituted alkyl group, R12 is an alkyl group and R3 and R4 independently of each other, are H or a substituent of an amino group, with the proviso that not both R3 and R4 are H
from a cyclohexene oxide of formula 
wherein R11 and R12 are as above.
The term alkyl in R11 has the meaning of a straight chain or branched alkyl group of 1 to 20 C-atoms, expediently of 1 to 12 C-atoms. Examples of such alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert.-butyl, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its isomers, undecyl and its isomers and dodecyl and its isomers.
This alkyl group can be substituted with one or more substituents as defined in e.g. WO 98/07685. Suitable substituents are alkyl having 1 to 20 C-atoms(as defined above), alkenyl having 2 to 20 C-atoms, cycloalkyl having 3 to 6 C-atoms, hydroxy, alkoxy having 1 to 20 C-atoms, alkoxycarbonyl having 1 to 20 C-atoms, F, Cl, Br, and J.
The preferred meaning for R11 is 1-ethylpropyl.
R12 here is a straight chain or branched alkyl group of 1 to 12 C-atoms, expediently of 1 to 6 C-atoms as exemplified above.
The preferred meaning for R12 is ethyl.
In the compound of formula (VII), the substituent of an amino group is as defined above Suitable substituents of amino groups are also described in, e.g., the WO 98/07685.
Preferred substituents of an amino group for R3 and R4 are alkanoyl groups, more preferably lower-alkanoyl with 1 to 6 C-atoms such as hexanoyl, pentanoyl, butanoyl (butyryl), propanoyl (propionyl), ethanoyl (acetyl) and methanoyl (formyl). Preferred alkanoyl group and therefore preferred meaning for R3 is acetyl and for R4 is H.
The most preferred 1,2-diamino compound of formula (I) or 4,5-diamino-shikimic acid derivative of formula (VII) therefore is the (3R,4R,5S)-5-amino-4-acetylamino-3-(1-ethyl-propoxy)-cyclohex-1-ene-carboxylic acid ethyl ester or the (3R,4R,5S)-5-amino-4-acetylamino-3-(1-ethyl-propoxy)-cyclohex-1-ene-carboxylic acid ethyl ester phosphate (1:1). The most preferred 1,2-epoxide of formula (II) or cyclohexene oxide of formula (VIII) therefore is the (1S,5R,6R)-5-(1-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester.
Step a)
Step a) comprises reacting a 1,2-epoxide of formula (II) with an amine of formula R5NHR6 to form the respective 2-aminoalcohol of formula (III).
The amine of formula R5NHR6 of step (a) is a primary or secondary amine which shows reactivity for opening the 1,2-epoxide ring.
R5 and R6 in the amine of formula R5NHR6 expediently is a straight chain or branched alkenyl of 2 to 6 C-atoms, optionally substituted benzyl or tri-substituted silyl methyl or heterocyclyl methyl.
The straight chain or branched alkenyl of 2 to 6 C-atoms preferably is allyl or an analog thereof such as allyl or an allyl group which is substituted on the xcex1, xcex2-or xcex3-carbon by one lower alkyl, lower alkenyl, lower alkynyl or aryl group. Suitable examples are, e.g., 2-methylallyl, 3,3-dimethylallyl, 2-phenylallyl, or 3-methylallyl. Preferred amines of formula R5NHR6 with the meaning of a straight chain or branched alkenyl of 1 to 6 C-atoms group therefore are allylamine, diallylamine or 2-methylallylamine, whereby allylamine is the most preferred.
Optionally substituted benzyl preferably is benzyl or benzyl analogs which are either substituted on the xcex1-carbon atom with one or two lower alkyl, lower alkenyl, lower alkynyl or aryl groups or substituted on the benzene ring with one or more lower alkyl, lower alkenyl, lower alkynyl, lower-alkoxy or nitro groups. Suitable examples are xcex1-methylbenzyl, xcex1-phenylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4-nitrobenzyl or 3-methylbenzyl. Preferred amines of formula R5NHR6 with the meaning of an optionally substituted benzyl group are benzylamine, dibenzylamine, methylbenzylamine, 2-methoxybenzylamine, 3-methoxybenzylamine or 4-methoxybenzylamine, whereby benzylamine is the most preferred.
Trisubstituted silyl methyl preferably is silyl methyl trisubstituted with aryl, lower alkyl, lower alkenyl and/or lower alkynyl groups. Suitable examples are trimethylsilyl, triethylsilyl, diphenylmethylsilyl, phenyldimethylsilyl or tert.-butyldimethylsilyl. Preferred amine of formula R5NHR6 with the meaning of tri-substituted silyl methyl is the trimethylsilyl methylamine.
Heterocyclyl methyl preferably is heterocyclyl methyl wherein either the methyl group is substituted with one or two lower alkyl, lower alkenyl, lower alkynyl or aryl groups or the heterocyclic ring is substituted with one or more lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy groups. Suitable examples are furfuryl or picolyl.
The most preferred amine of formula R5NHR6 is allylamine.
The amine of formula R5NHR6 is generally used in a molar amount of 1.0 to 3.0 equivalents, preferably of 1.5 to 2.5 equivalents, based on one equivalent of the 1,2-epoxide of formula (II).
Step (a) can be performed without a catalyst under normal or elevated pressure, however, the reaction time of step (a) can in general be significantly reduced in the presence of a catalyst.
Suitably the catalyst is a metal catalyst or a magnesium halide.
Convenient metal catalysts known to catalyze ring opening reactions of 1,2-epoxides with amines e.g. are lanthanide compounds such as lanthanide trifluoromethanesulfonates like Yb(OTf)3, Gd(OTf)3 and Nd(OTf)3 (M. Chini et al., Tetrahedron Lett., 1994, 35, 433-436), samarium iodides (P. Van de Weghe, Tetrahedron Lett., 1995, 36, 1649-1652) or other metal catalysts such as amide cuprate reagents (Y. Yamamoto, J. Chem. Soc., Chem. Commun., 1993, 1201-1203) and Ti(O-i-Pr)4 (M. Caron et al., J. Org. Chem., 1985, 50, 1557 and M. Mxc3xcller, et al., J. Org. Chem., 1998, 68, 9753).
As a rule the ring opening with metal catalysts is carried out in the presence of an inert solvent e.g. in tetrahydrofuran at temperatures between 20xc2x0 C. and 150xc2x0 C.
In accordance with the present invention, the magnesium halides are the preferred catalysts for the ring opening of 1,2-epoxides with amines. The term xe2x80x9cmagnesium halide derivativexe2x80x9d here denotes anhydrous or hydrated magnesium chloride, magnesium bromide or magnesium iodide, or an etherate, in particular a dimethyl etherate, a diethyl etherate, a dipropyl etherate, or a diisopropyl etherate thereof.
Magnesium bromide diethyl etherate is the most preferred catalyst.
The magnesium halide is suitably used in a molar amount of 0.01 to 2.0 equivalents, preferably of 0.15 to 0.25 equivalents, based on one equivalent of the 1,2-epoxide of formula (II).
Suitable solvents for the magnesium halide catalysis are protic solvents such as ethanol or methanol, or preferably an aprotic solvent such as tetrahydrofuran, dioxane, tert.-butyl methyl ether, diisopropylether, isopropylacetate, ethylacetate, methylacetate, acetonitrile, benzene, toluene, pyridine, methylene chloride, dimethylformamide, N-methylformamide and dimethylsulfoxide or mixtures thereof.
The aprotic solvent is preferably selected from tetrahydrofuran, diisopropylether, tert.-butyl methyl ether, acetonitrile, toluene or a mixture thereof, most preferably is a mixture of tert.-butyl methyl ether and acetonitrile.
Magnesium halide catalysis is advantageously carried out at temperatures between 0xc2x0 C. and 200xc2x0 C., preferably between 50xc2x0 C. and 150xc2x0 C.
The respective 2-aminoalcohol of formula (III) can after the reaction has been finished be isolated and if so desired purified by methods known to those skilled in the art.
Step b)
Step b) comprises converting the 2-aminoalcohol of formula (III) into a 2-aminoalcohol of formula (IV).
The conversion in step b), is dependent on the residue R5 and R6.
If R5 and R6 independently of each other are straight chain or branched alkenyl of 2 to 6 C-atoms, the conversion is an isomerization/hydrolysis performed in the presence of a metal catalyst.
If R5 and R6 independently of each other are optionally substituted benzyl or heterocyclyl methyl, the conversion is a hydrogenolysis performed with hydrogen in the presence of a metal catalyst; or
If R5 and R6 independently of each other are tri-substituted silyl methyl, the conversion is an oxidative cleavage.
The fact that the preferred meaning for R5 and R6 are straight chain or branched alkenyl of 2 to 6 C-atoms as outlined above at step a) isomerization/hydrolysis is the preferred method for the conversion in step b).
Isomerization/hydrolysis accordingly takes place in the presence of a suitable metal catalyst, expediently a precious metal catalyst such as Pt, Pd or Rh either applied on an inert support such as charcoal or alumina, or in complexed form. A preferred catalyst is 5 to 10% palladium on carbon (Pd/C).
The catalyst is suitably used in an amount of 2 to 30 wt. %, preferably, 5 to 20 wt. % relating to the 2-aminoalcohol of formula (III).
The isomerization/hydrolysis is advantageously carried out in an aqueous solvent. The solvent itself can be protic or aprotic. Suitable protic solvents are e.g. alcohols such as methanol, ethanol or isopropanol. Suitable aprotic solvent is e.g. acetonitrile or dioxane.
The reaction temperature is preferably chosen in the range of 20xc2x0 C. and 150xc2x0 C.
It was found that isomerization/hydrolysis is preferably effected in the presence of a primary amine.
Primary amines suitably used are ethylenediamine, ethanolamine, or suitable derivatives of these primary amines mentioned hereinbefore. A particularly interesting primary amine is ethanolamine.
The primary amine is suitably used in an amount of 1.0 to 1.25 equivalents, preferably of 1.05 to 1.15 equivalents relating to the 2-aminoalcohol of formula (III).
As mentioned above, if R5 and R6 are, independently, optionally substituted benzyl or heterocyclyl methyl, the conversion is a hydrogenolysis performed in the presence of a metal catalyst with hydrogen. Hydrogenolysis conditions are well known in the art and described e.g. in Green, T., xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Chapter 7, John Wiley and Sons, Inc.,1991, 364-365.
Hydrogenolysis accordingly takes place in the presence of a suitable metal catalyst, expediently a precious metal catalyst such as Pt, Pd or Rh either applied on an inert support such as charcoal or alumina, or in complexed form. A preferred catalyst is 5 to 10% palladium on carbon (Pd/C). The catalyst is suitably used in an amount of 2 to 30 wt. %, preferably 5 to 20 wt. % relating to the 2-aminoalcohol of formula (III).
Hydrogenolysis advantageously is carried out in an aqueous solvent. The solvent itself can be protic or aprotic. Suitable protic solvents are, e.g., alcohols such as methanol, ethanol or isopropanol. Suitable aprotic solvents are, e.g., acetonitrile or dioxane. The reaction temperature is preferably chosen in the range of 20xc2x0 C. and 150xc2x0 C.
As mentioned above, if R5 and R6, independently of each other, are tri-substituted silyl methyl, the conversion is an oxidative cleavage.
Expediently the reaction is performed in the presence of a haloimide.
Haloimides suitable for this reaction are N-chloro-succinimide, N-bromosuccinimide or N-chlorobenzene sulfonamide (chloramine-T).
The reaction can be performed in the presence of an inert solvent at temperatures of 20xc2x0 C. to 150xc2x0 C.
In order to completely hydrolyze any imines that may have formed in step b) the reaction mixture is usually treated with an acid e.g. with sulfuric acid or hydrochloric acid.
Step c)
Step c) comprises the transformation of the 2-aminoalcohol of formula (IV) into a 1,2-diamino compound of formula (V)
In detail step c) comprises the steps,
(c1) protecting the free amino group of the 2-aminoalcohol of formula (IV) with a substituent of an amino group;
(c2) activating the hydroxy group into a leaving group, and
(c3) deprotecting the amino group and treating the reaction product with an amine of formula R5NHR6, wherein R5 and R6 are as above to form a 1,2-diamino compound of formula (V).
Step c1)
In accordance with the present invention, the term xe2x80x9csubstituent of an amino groupxe2x80x9d refers to a substituent conventionally used to hinder the reactivity of the amino group. As stated above, suitable substituents are described in Green T., xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Chapter 7, John Wiley and Sons, Inc.,1991, 315-385.
Particularly interesting is the conversion of the amino group with a carbonyl group containing compound to form an imine, a so called xe2x80x9cSchiff basexe2x80x9d.
Also acyl substituents which are formed by treating of the 2-aminoalcohol of formula (IV) with an acylating agent may be utilized to hinder the reactivity of the amino group.
Formation of a Schiff base is the preferred method for the conversion of the free amino group of the 2-aminoalcohol of formula (IV) into a substituted amino group.
Carbonyl compounds suitable to form a Schiff base are either aldehydes or ketones. Both the aldehydes and the ketones can be aliphatic, alicyclic or aromatic, preferably aromatic.
Examples of suitable aliphatic aldehydes are propionaldehyde, 2-methylpentenal, 2-ethylbutyraldehyde, pivaldehyde, ethyl glyoxylate and chloral. An example of an alicyclic aldehyde is cyclopropan carbaldehyde. Examples of suitable aromatic aldehydes are furfural, 2-pyridinecarboxylaldehyde, 4-methoxybenzaldehyde, 3-nitrobenzaldehyde, a benzaldehyde sulfonate, a furfural sulfonate, and benzaldehyde. A particularly interesting aromatic aldehyde is benzaldehyde.
Examples of suitable aliphatic ketones are 1,1-dimethoxyacetone and 1,1-diethoxyacetone. Examples of suitable alicyclic ketones are cyclopentanone, cyclohexanone, cycloheptanone, 2-ethyl cyclohexanone and 2-methyl-cyclopentanone. An example of an aromatic ketone is acetophenone.
A preferred carbonyl containing compound is benzaldehyde.
The carbonyl containing compound is expediently used in an amount of 1.0 to 1.50, preferably 1.10 to 1.40 equivalents relating to the 2-aminoalcohol of formula (IV).
Formation of the Schiff base is advantageously performed in a protic or aprotic solvent, preferably in an aprotic solvent.
Suitable aprotic solvents are for example tetrahydrofuran, dioxane, tert.-butyl methyl ether, diisopropylether, isopropylacetate, ethylacetate, methylacetate, acetonitrile, benzene, toluene, pyridine, methylene chloride, dimethylformamide, N-methylformamide and dimethylsulfoxide. A preferred aprotic solvent is tert.-butyl methyl ether.
The water formed is usually removed by azeotropic distillation.
Formation of the Schiff base is advantageously carried out at temperatures between 30xc2x0 C. and 180xc2x0 C., preferably between 60xc2x0 C. and 140xc2x0 C.
If step c1) comprises acylation, as mentioned above, the 2-aminoalcohol of formula (IV) is transformed into a 2-acyl aminoalcohol.
The acylating agent can be a carboxylic acid, or an activated derivative thereof, such as an acyl halide, a carboxylic acid ester or a carboxylic acid anhydride. Suitable acylating agents are acetylchloride, trifluoracteylchloride, benzoyl chloride or acetic anhydride. A preferred acyl group is formyl. Suitable formylating agent therefore is e.g. a formic acid mixed anhydride such as for example formic acid acetic acid anhydride, or a formic acid ester, such as ethyl formate or methyl formate or a formic acid active ester such as cyanomethyl formate.
The acylating agent is suitably used in an amount of 1.0 to 1.3, preferably 1.1 to 1.2 equivalents relating to the 2-aminoalcohol of formula (IV).
The choice of solvent is not critical as long as it does not interfere with the reactants. It was found that e.g. ethylacetate is a suitable solvent. The reaction can however also be performed without solvent i.e. in the presence of the respective acylating agent applied in excess.
Reaction temperature usually is in the range of xe2x88x9220xc2x0 C. to 100xc2x0 C.
Step c2)
Step (c2) comprises activating the hydroxy group into a leaving group, thereby forming an O-substituted 2-aminoalcohol.
Compounds and methods for effecting this transformation are well known in the art and described e.g. in xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, ed. March J., John Wiley and Sons, New York, 1992, 353-357.
It was found that the hydroxy group is preferably transformed into a sulfonic acid ester by treating the hydroxy group with a sulfonylating agent.
Agents commonly used for producing sulfonic acid esters e.g. are the halogenides or the anhydrides of the following sulfonic acids: methane sulfonic acid, p-toluenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid or trifluoromethanesulfonic acid.
Preferred sulfonylating agents are halogenides or anhydrides of methane sulfonic acid such as methane sulfonylchloride.
The sulfonylating agent is expediently added in an amount of 1.0 to 2.0 equivalents relating to one equivalent of the 2-aminoalcohol of formula (IV).
Preferably, the reaction in step c2) takes place in an inert solvent, more preferably, in the same solvent which has been used in the previous step c1) and at a reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C.
Step (c3)
Step (c3) comprises deprotecting the amino group, i.e., cleaving the substituent of the amino group. Any conventional method and conditions for cleaving the substituent of the amino group can be utilized. These conditions also remove the leaving group which results in the formation of an aziridine intermediate of formula 
wherein R1, R1xe2x80x2, R2 and R2xe2x80x2 are as above.
This aziridine intermediate can be isolated, but preferably, is reacted in situ with an amine of formula R5NHR6, wherein R5 and R6 are as defined above, to form the 1,2-diamino compound of formula (V).
The amine of formula R5NHR6 is the very same as applied in step a). Also the same preferences are applicable as for the amine in step a). Accordingly the most preferred amine of formula R5NHR6 used for step c3) is allylamine.
The course of the reaction in step c3) and the respective reaction conditions mainly depend on the kind of protection of the amino group in step c2).
Having a Schiff base the transformation is directly effected with the amine of formula R5NHR6, whereby having an acetyl group, prior to the transformation with the amine of formula R5NHR6 a deacylation treatment has to take place first.
In case of a Schiff base, the amine of formula R5NHR6 is used in an amount of at least two equivalents, preferably of 2.0 to 5.0, more preferably of 2.5 to 4.0 equivalents relating to one equivalent of the 2-aminoalcohol of formula (IV).
The solvent used in this reaction step (c3) is as a rule the same as of the previous step c2). Accordingly protic or aprotic solvents, preferably aprotic solvents, such as for example tetrahydrofuran, dioxane, tert.-butyl methyl ether, diisopropylether, isopropylacetate, ethylacetate, methylacetate, acetonitrile, benzene, toluene, pyridine, methylene chloride, dimethylformamide, N-methylformamide and dimethylsulfoxide can be used. A preferred solvent is tert.-butyl methyl ether.
In case of a Schiff base the conversion is advantageously carried out at a temperature of 60xc2x0 C. to 170xc2x0 C., preferably of 90xc2x0 C. to 130xc2x0 C. and applying normal pressure to 10 bars.
When the substituted amino group is acyl, prior to the treatment with the amine of formula R5NHR6, deacylation has to take place as mentioned above.
Deacylation can easily be effected under acidic conditions, e.g., using sulfuric acid, methanesulfonic acid or p-toluenesulfonic acid.
Thereby the respective sulfonate or sulfate salt of the O-substituted 2-aminoalcohol is formed.
The amine of the formula R5NHR6 is then suitably used in an amount of 1.0 to 5.0 equivalents, preferably of 2.0 to 4.0 equivalents relating to one equivalent of the 2-aminoalcohol of formula (IV).
The choice of solvents is about the same as for the conversion of the Schiff base, preferably ethyl acetate or tert.-butyl methyl ether.
The reaction temperature is chosen between 60xc2x0 C. and 170xc2x0 C., preferably between 90xc2x0 C. and 130xc2x0 C. and the pressure is selected between normal pressure and 10 bar.
When operating with a Schiff base step c) thus can efficiently be performed in a one pot synthesis without isolating the intermediates.
Step d)
Step d) comprises the acylation of the free amino group in position 1 of the 1,2-diamino compound of formula (V) to form an acylated 1,2-diamino compound of formula (VI).
Acylation can be effected under strong acidic conditions by treating the 1,2-diamino compound of formula (V) with acylating agents known to the skilled in the art. The acylating agent can be an aliphatic or aromatic carboxylic acid, or an activated derivative thereof, such as an acyl halide, a carboxylic acid ester or a carboxylic acid anhydride. Suitable acylating agents are preferably acetylating agents such as acetylchloride, trifluoracteylchloride or acetic anhydride. A suitable aromatic acylating agent is benzoylchloride. Strong acids suitably used e.g. are mixtures of methane sulfonic acid and acetic acid or sulfuric acid and acetic acid.
Acylation however can also take place under non-acidic conditions using e.g. N-acetyl imidazole or N-acetyl-N-methoxy acetamide.
Preferably however the acylation takes place under acidic conditions using a mixture of 0.5 to 2.0 equivalents of acetic anhydride, 0 to 15.0 equivalents of acetic acid and 0 to 2.0 equivalents of methanesulfonic acid in ethyl acetate.
An inert solvent such as tert.-butyl methyl ether may be added, it is however also possible to run the reaction without addition of any solvent.
The temperature is as a rule chosen in the range of xe2x88x9220xc2x0 C. to 100xc2x0 C.
Step e)
Step e) comprises deprotecting the amino group in position 2 and, if desired, further transforming the resulting 1,2-diamino compound of formula (I) into a pharmaceutically acceptable addition salt.
Deprotecting the amino group, i.e., removal of the substituent of the amino group in position 2 takes place following the same methods and applying the same conditions as described in step b).
The conversion in step e), accordingly is also dependent on the residue R5 and R6. Therefore,
if R5 and R6 independently of each other are straight chain or branched alkenyl of 2 to 6 C-atoms, the conversion is a hydrolysis performed in the presence of a metal catalyst,
if R5 and R6 independently of each other are optionally substituted benzyl or heterocyclyl methyl, the conversion is a hydrogenolysis performed with hydrogen in the presence of a metal catalyst or
if R5 and R6 independently of each other is tri-substituted silyl methyl, the conversion is an oxidative cleavage.
The same preferences as for step b) are valid for step e).
For any further details reference is made to step b).
As a rule the 1,2-diamino compound of formula (I) can be isolated e.g. by evaporation and crystallization, but it is preferably kept in e.g. an ethanolic solution and then further transformed into a pharmaceutically acceptable addition salt following the methods described in J. C.Rohloffet al., J.Org.Chem.,1998, 63, 4545-4550; WO 98/07685).
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane sulfonic acid, p-toluenesulfonic acid and the like.
The salt formation is effected in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, maleates, succinates, methansulfonates, p-toluenesulfonates and the like are examples of such salts.
Preferred pharmaceutically acceptable acid addition salt is the 1:1 salt with phosphoric acid which can be formed preferably in ethanolic solution at a temperature of xe2x88x9220xc2x0 C. to 50xc2x0 C.
The invention also relates to the following new intermediates: 
wherein R11 and R12 are as stated above, or an addition salt thereof.
A preferred representative of the compounds of formula (X) is (3R,4S,5R)-5-amino-3-(1-ethyl-propoxy)-4-hydroxy-cyclohex-1-ene carboxylic acid ethylester (R11=1-ethyl-propyl, R12=ethyl) 
wherein R5, R6, R11 and R12 are as stated above, or an addition salt thereof.
Preferred representatives of compounds of formula (XI) are (3R,4S,5R)-5-allylamino-3-(1-ethylpropoxy)-4-hydroxy-cyclohex-1-ene carboxylic acid ethylester (with R11=1-ethyl-propyl, R12=ethyl, R5=H and R6=allyl) and (3R,4R,5R)-5-formylamino-3-(1-ethylpropo)-4-hydroxy-cyclohex-1-en carboxylic acid ethylester (with R11=1-ethylpropyl, R12=ethyl, R5=H and R6=formyl) 
wherein R3, R4, R5, R6, R11 and R12 are as stated above or an addition salt thereof.
Preferred representatives of compounds of formula (XII) are (3R,4R,5S)-4-acetylamino-5-allylamino-3-(1-ethyl propoxy)-cyclohex-1-ene carboxylic acid ethylester (with R11=1-ethyl propyl, R12=ethyl, R5=H, R6=allyl, R3=H, R4=acetyl) and (3R,4R,5S)-4-amino-5-allylamino-3-(1-ethylpropoxy)-cyclohex-1-en carboxylic acid ethyl ester (with R11=1-ethylpropyl, R12=ethyl, R5=H, R6=allyl, R3=H, R4=H) 
wherein R5, R6, R11 and R12 are as stated above and R13 is a sulfonyl group, or an addition salt thereof.
Preferred representatives of compounds of formula (XIII) are (3R,4R,5R)-5-formylamino-4-methanesulfonyl-3-(1-ethylpropoxy)-cyclohex-1-ene carboxylic acid ethylester (with R11=1-ethylpropyl, R12=ethyl, R5=H, R6=formyl, R13=methanesulfonyl) and (3R,4R,5R)-5-amino-4-methanesulfonyl-3-(1-ethylpropoxy)cyclohex-1-en carboxylic acid ethylester methansulfonate (1:1) (with R11=1-ethylpropyl, R12=ethyl, R5=H, R6=H, R13=methanesulfonyl)
The invention also relates to a new process for preparing a 2-aminoalcohol of formula
wherein R1, R1xe2x80x2, R2 and R2xe2x80x2, independently from each other, are H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl,heterocyclyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, aryl, or aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, or
R1 and R2, R1 and R2xe2x80x2, R1xe2x80x2 and R2 or R1xe2x80x2 and R2xe2x80x2 taken together with the two carbon atoms to which they are bound, are a carbocyclic or heterocyclic ring system, or
R1 and R1xe2x80x2 or R2 and R2xe2x80x2 taken together with the carbon atom to which they are bound, are a carbocyclic or heterocyclic ring system,
with the proviso that at least one of R1, R1xe2x80x2, R2 and R2xe2x80x2 is not H, and
R5 and R6, independently of each other, are H or a substituent of an amino group, with the proviso that not both R5 and R6 are H, comprising
treating a 1,2-epoxide of formula
xe2x80x83wherein R1, R1xe2x80x2, R2 and R2xe2x80x2 are as above
with an amine of formula R5NHR6 wherein R5 and R6 are as above in the presence of a magnesium halide catalyst.
This process corresponds to the preferred method of step a) as described herein before. Accordingly the respective description of step a) is incorporated herein by reference.
A preferred amine of formula R5NHR6 accordingly is allylamine, diallylamine, benzylamine, dibenzylamine or trimethylsilyl amine more preferably allylamine and preferred magnesium halide catalyst is magnesium bromide diethyl etherate.
The invention further relates to a new process for the transformation of the 2-aminoalcohol of formula (IV)
wherein R1, R1xe2x80x2, R2 and R2xe2x80x2 are as above, into a 1,2-diamino compound of formula (V)
wherein R1, R1xe2x80x2, R2, R2xe2x80x2, R5 and R6 are as above.
This process corresponds to step c) as described herein before. Accordingly the whole description of step c) is incorporated herein by reference. Also the same preferences as given under c) apply here.
As stated above, this process comprises the steps,
(c1) protecting the free amino group of the 2-aminoalcohol of formula (IV) with a substituent of an amino group;
(c2) activating the hydroxy group into a leaving group, and
(c3) deprotecting the amino group and treating the reaction product with an amine of formula R5NHR6, wherein R5 and R6 are as above into a 1,2-diamino compound of formula (V).
In a preferred embodiment this process is characterized by
c1) forming a Schiff base by reacting the 2-aminoalcohol of formula (IV) with a carbonyl group containing compound, preferably with benzaldehyde,
c2) treating the hydroxy group with a sulfonylating agent to form a sulfonic acid ester, preferably, a methanesulfonic acid ester, and
c3) deprotecting the amino group of the 2-aminoalcohol of formula (IV) to form an aziridine intermediate, and treating the aziridine intermediate with allylamine, diallylamine, benzylamine, dibenzylamine or trimethylsilyl amine, preferably with allylamine to form the 1,2-diamino compound of formula (V).